An effective drug regimen remains elusive for the treatment of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, fronto-temporal dementia, as well as brain injury, such as traumatic brain injury (TBI) and related cognitive deficits, and CTE (chronic traumatic encephalopathy).
To date, multiple Phase III clinical trials for the treatment of AD and other neurodegenerative diseases have been unsuccessful, not necessarily because they did not engage their target, but the target may be dissociated from the desired therapeutic outcome, namely retention of cognitive abilities. The majority of the clinical trials for AD therapies have focused on amyloid precursor protein (APP) processing, and while amyloid levels were reduced in many of the clinical trials, there was no positive effect on memory performance. Furthermore, complications such as toxicity problems and worsened cognitive functions have emerged (Golde et al., 2009, Science 324:603-604; Kerchner & Boxer, 2010, Expert Opinion on Biological Therapy 10:1121-1130; Chakroborty and Stutzmann, 2013 Dec. 6, Eur J Pharmacol., pii: S0014-2999(13)00883-2. doi: 10.1016/j.ejphar.2013.11.012 [Epub ahead of print]). A possible reason why these compounds did not succeed is that they were administered too late after the cellular and synaptic pathology occurred, and clearing amyloid at this stage would not improve synaptic damage.
An alternative approach to treatment of AD and other neurodegenerative diseases is to target aberrant pathogenic calcium signaling cascades. Stabilization of calcium signaling targets a pathogenic mechanism that is tied to many major features and risk factors of neurodegenerative diseases. Rather than targeting a single diagnostic endpoint, such as amyloid aggregation, this strategy aims to normalize a pathogenic accelerant—namely, sustained calcium dyshomeostasis—that is linked to amyloid pathology, tau hyperphosphorylation, apoptosis, synaptic pathophysiology, and memory deficits.
Calcium signaling in neurons is fundamental to numerous critical functions, including gene transcription, cell death, synaptic integrity, synaptic plasticity, and memory encoding. For example, early increases in endoplasmic reticulum (ER) calcium release through ryanodine receptor (RyR) channels occur in a host of AD models, and in cells from familial and sporadic AD patients. Notably, RyR isoform 2 (RyR2) expression is altered in AD patients and mouse models as well. Neuronal calcium dyshomeostasis is linked to all the major risk factors, histopathological features, synaptic deficits, and cognitive impairments that define AD; therefore, stabilizing ER calcium can broadly impact a range of AD-linked pathologies. Several recent studies have demonstrated that treating neurons from AD mice with dantrolene, a clinically available RyR stabilizer, reduces amyloid deposition, improves memory performance, reverses intracellular calcium alterations, and normalizes RyR expression (Chakroborty and Stutzmann, 2013 Dec. 6, Eur J Pharmacol., pii: S0014-2999(13)00883-2. doi: 10.1016/j.ejphar.2013.11.012 [Epub ahead of print]; Oules et al., 2012, Journal of Neuroscience 32:11820-11834). Similar therapeutic effects are also evident with models of traumatic brain injury (TBI). Chronic dantrolene treatment in TgCRND8 mice after exposure to a mild TBI markedly reduces the amount of pathological tau phosphorylation (FIG. 5). However, dantrolene may be pathogenic; chronic oral treatment (10+ months) with dantrolene was found to increase amyloid pathology (Zhang et al., 2010, Journal of Neuroscience 30:8566-8580).
Thus, there is a need in the art for novel compounds capable of stabilizing ryanodine receptor channels.